Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

Abstract

Abstract Background Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options. Methods Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure, oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits. Results Mutant animals displayed significantly lower body weights, reduced inguinal fat pad mass, but normal liver weights in comparison to unaffected littermates. Biochemically, they were characterized by pronounced hypoglycemia accompanied with hypoinsulinemia and significantly lower total cholesterol, high density lipoprotein and triglyceride levels. Moreover, energy expenditure was significantly higher in mutant compared to littermate mice. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals. Conclusion These data are suggestive of the presence of compensatory mechanisms in the context of this specific mutation, ensuring sufficient mitochondrial DNA levels that do not further influence phenotype and survival.